CN1058969A - The preparation method of deoxynucleoside - Google Patents
The preparation method of deoxynucleoside Download PDFInfo
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- CN1058969A CN1058969A CN91104951A CN91104951A CN1058969A CN 1058969 A CN1058969 A CN 1058969A CN 91104951 A CN91104951 A CN 91104951A CN 91104951 A CN91104951 A CN 91104951A CN 1058969 A CN1058969 A CN 1058969A
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- 0 CC1C(C*)N=C(CC=C(C(C)=C(C(C)=O)O)C(O)=C)C1 Chemical compound CC1C(C*)N=C(CC=C(C(C)=C(C(C)=O)O)C(O)=C)C1 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a kind of dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycoside compound by protection with contain the substituent organo-aluminium compound halogenated compositions prepared in reaction 2 of (it shows bigger solubleness than AlF3 in traditional solvent) ' with 3 '-(2 of halogen-replacement ', 3 '-di-deoxynucleoside) improved method.
Description
The present invention relates to from corresponding dehydration di-deoxynucleoside counterpart synthetic 3 '-(halogen-replacement) 2 ', 3 '-di-deoxynucleoside and 2 '-(halogen-replacement) 2 ', 3 '-novel method of di-deoxynucleoside.
Acquired immune deficiency syndrome (AIDS) has reflected that general immunity suppresses the imbalance of mechanism, and it is to be the caused communicate illness of Retro-Virus of human immunity deficiency disease virus (HIV) by title.Because HIV is a kind of Retro-Virus, the reversed transcriptive enzyme of virus is a kind of selectivity target of antiviral agent seemingly.Thus, reported a series of different reverse transcriptase inhibitors already and can be used as the vigor that duplicates that there is anti-HIV the inside and outside with different chemical structures.
In these reverse transcriptase inhibitors, 2 ', 3 '-the dideoxy ribonucleoside specially by report as having obvious inhibiting activity at external anti-HIV.
2 ', 3 '-report of dideoxy ribonucleoside product in, 3 '-azido--2 ', 3 '-dideoxy chest (gland pyrimi piperidine deoxidating nucleus) glycosides (AZT), with 3 '-deoxidation-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides (relate to simultaneously as 2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides or FLT) show to have the selectivity HIV (human immunodeficiency virus)-resistant activity especially.Compound 3 '-azido--2 ', 3 '-dideoxy chest (gland nuclear pyrimidine) glycosides (AZT) is a kind of effective inhibitor that the commercial HIV that buys causes the cytopathy sex change.Yet, 3 '-deoxidation-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides has according to reports than AZT bigger activity.So, to compound 3 '-deoxidation-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides (FLT) and other 2 ' or 3 '-deoxynucleoside that fluoro-replaces might be interested especially as the medicament of treatment acquired immune deficiency syndrome (AIDS).
Yet, the investigator runs into some problem in preparation fluoro nucleosides, comprise: (1) needs the reagent of lower concentration and matrix to cause low-down productive rate in fluorination process, and (2) are used in obtain inconsistent result when reagent in the common fluorination process has minimum solubleness and (3) to adopt the method for some known technology in solvent.
From G.Etzold, R.Hintsche, the Tetrahedron 27(1971 of G.Kowollik and P.Langen) learn the synthetic method of FCT among the PP.2463-2472.They disclose 2,3 '-dehydration-1-(2-deoxidation-β-D-wood furanoside base) thymus pyrimidine and HF react, and uses AlF
3Obtain the product of 28% productive rate in 150-170 ℃ of reaction as catalyzer.Simultaneously, their preparation that discloses it be by 3 '-O-methylsulfonyl-thymidine and KHF
2Or NH
4F obtains the product of 14% productive rate in 190 ℃ of reactions.In other document, the author from 2,3 '-dehydration-1-(2-deoxidation-5-O-methylsulfonyl-β-D--penta furanoside base of reviving) thymus pyrimidine HF-AlF
3Synthetic 3 '-deoxidation-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides (J.Prakt, Chem., 315,895,1937).
At United States Patent (USP) 3,775, in 397, same author reported 3 '-deoxidation-3 '-preparation of fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.By 2,3 '-dehydration-1-(2-deoxidation-β-D-wood furanoside base) thymus pyrimidine and 30cm
3The 4-6%HF solution in no Shui diox in airtight container, obtain product up to 46% productive rate in 90 ℃ of reactions.Yet the present inventor attempts to repeat this method, but does not produce the product of any significant amounts.
Other closely-related compound is fluoridized with diethylamino sulphur trifluoride (DAST).
All known technologies relate to the synthetic of laboratory scale purpose compound.Yet, according to the method for known technology proof and be not suitable for this compound of scale operation, because the productive rate of the reaction of known technology is unpractiaca to scale operation.Because the low solubleness fluorizating agent of reagent need be used very rare concentration and big volume (as: 0.5-1.0%AlF
3) and need high-temperature.In addition, the reaction of announcement normally obtains increasing and fails the impurity (pollutent) that branch leaves away.With the method for known technology, be difficult to obtain consistent component and estimable productive rate.Use AlF
3/ HF or KHF
2Or NH
4The productive rate that F reported especially is difficult to duplication of production on the constant radix.Simultaneously, the prestige that becomes security with some reagent helps, especially scale operation (as: DAST).The existence of these problems causes known technology to be unsuitable for the large-scale production of The compounds of this invention.
So, need a kind of be suitable for scale operation 2 ' and 3 '-method of (fluoro-replaces) di-deoxynucleoside, this method has overcome agent dissolves degree problem and has obtained product with the constant repeatability mode of production with good productive rate.
Surprisingly, find the organoaluminum of the replacement of the following structural formula of employing:
R, K and M the following is regulation in the formula, cause improving significantly on turnout, productive rate and the operability of reaction.In addition, need not further processing such as: the chromatography process obtains high purity product.Adopt the organoaluminum of replacement of the present invention to make to be reflected at smaller volume and lower temperature is carried out, then cause with good, constant can obtain 2 with recurring ' or 3 '-(fluoro-replaces) di-deoxynucleoside.
The object lesson of the present invention of the machine aluminium compound upperseat concept of the replacement of adopting, its solvability in organic solvent is bigger than their inorganic counterparts, to guarantee the possibility of nucleophilic substitution on nucleosides.
Especially; the present invention relates to a kind of preparation 3 '-(halogen-replacement)-2 '; 3 '-di-deoxynucleoside and 2 '-(halogen-replacement)-2 ', 3 '-method of di-deoxynucleoside, its dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycoside compound by protection compares AlF with containing in by solvent
3Show the halogenated compositions prepared in reaction of the organo-aluminium compound of the replacement of solubleness greatly.
More specifically, the present invention relates to prepare be selected from 2 of following structural formula ' or 3 '-(halogen-replacement)-2 ', 3 '-improvement and the method for di-deoxynucleoside:
Z is oxygen or CH in the formula
2;
R
1And R
2Can be for identical or different, and be selected from the aryl that comprises hydrogen, low alkyl group, halogen, alkenyl, aryl and replacement;
R
3For being selected from hydrogen and halogen; And X is a halogen; Its method comprises the steps:
(A) with structural formula (I a) or the compound of (I b):
R in the formula
1, R
2And R
3For as above-mentioned defined and P be hydrogen or suitable blocking group, it can be selected from and comprise that trityl group, methoxyl group trityl group, ethanoyl, valeryl, methylsulfonyl or trialkyl first reagent silica-based and following structural formula reacts
H-X
X is a halogen in the presence of the addition reagent of following structural formula in the formula:
R is selected from and comprises (C in the formula
1-C
12) alkyl side chain or non-side chain, (C
1-C
12) phenyl of alkoxyl group side chain or non-side chain, phenyl or replacement, hydrogen, carboxyl, benzyl, enol base, beta-diketon acidic group, carbonyl, alkenyl, (C
1-C
12) group of sulfur phenenyl of sulfane base side chain or non-side chain, sulfur phenenyl or replacement; K and M can be identical or different and can be same as the R group or for a kind of halogen for being selected from; With structural formula (2a) or the intermediate (2b) that is protected:
And when P is not hydrogen in (B) formula then, remove blocking group P with obtain 3 '-(halogen-replacement) 2 ', 3 '-di-deoxynucleoside or 2 '-(halogen-replacement) 2 ', 3 '-di-deoxynucleoside.When P is hydrogen, do not need to remove blocking group P.
Preparation 2 ' or 3 '-(halogen-replacements) 2 ', 3 '-method of di-deoxynucleoside, usually can be by the reaction process summary of following flow diagram I.
In this reaction; the dehydration nucleosides (1a) of protection or (1b) in step (A), react the nucleosides (2a) of the replacement be protected or (2b); they can be in step (B) process by report convert to de-protected 3 '-(replacement) 2 '; 3 '-di-deoxynucleoside (3a) and 2 '-(replacement) 2 ', 3 '-di-deoxynucleoside.
Below be the schema I:
The reacting flow chart I
The reference flow sheet I, substituting agent H-X that step (A) expression is suitable and dehydration nucleosides (1a) or (1b) between, reaction is with the nucleosides (2a) that forms the replacement of protecting and (2b) in the presence of the organoaluminum reagent that replaces.The reaction of step (A) is to carry out in inert solvent.Suitable adoptable inert solvent comprises tetrahydrofuran (THF), acetone, diox, chloroform, methylene dichloride, ether, oil of mirbane, methyl-sulphoxide, 1,2-ethylene dichloride, 1,2-glycol dimethyl ether, toluene and acetonitrile and/or their composition.Preferably, this inert solvent is anhydrous.Temperature of reaction can be 0 ° to 130 ℃ scope.The most normally, the blended reactant reacts then at-5 ℃ and 40 ℃ and is undertaken by heating between 40 ℃ to 115 ℃ at airtight container.Preferably, react between 60 ℃ and 95 ℃ by the reacting by heating thing.The common reaction times was from about 1 hour to about 24 hours, but the highest general productive rate can obtain between 3 and 6 hours.
As mentioned above, X is a halogen and best be fluorine.The organoaluminum reagent that replaces can be selected from those that the said structure formula mentioned.Adoptable special reagent comprises two or trialkylaluminium, Acetyl Acetone aluminium, aluminum isopropoxide, three-just-hexyl aluminium, triphenyl aluminum, tribenzyl aluminium or 3-ethanoyl aluminium glycyrrhetate salt.
Mean fluorine, chlorine, bromine or iodine as term used herein " halogen ".The substituting group of " aryl of replacement " that relates in term, " phenoxy group of replacement ", " phenyl of replacement " or " sulfur phenenyl of replacement " can be halogen, (C
1-C
6) alkyl or alkoxyl group.
Advantageously, used reagent is for being dissolved in HF in the suitable inert solvent with 0.01 to 15% mol ratio.HF can advantageously be dissolved in diox, 1, in 2-glycol dimethyl ether or the tetrahydrofuran (THF).
In preferable example, especially when the dehydration nucleosides with protection was used as matrix, the blended solvent systems comprised productive rate and the high-caliber purity that 30% pyridine and 70%HF are improved as reaction mixture.Simultaneously, when in reaction mixture, adding two fluoro hydrogen ammonium (NH
4FHF) or during different amine compound, also obtain good result.
As mentioned above, R
1For being selected from the aryl of hydrogen, low alkyl group, halogen, alkenyl, aryl or replacement; R
2For being selected from the aryl of hydrogen, low alkyl group, halogen, alkenyl, aryl and replacement; And R
3For being selected from hydrogen and halogen.
In the preferable compound F 17-hydroxy-corticosterone LT of preparation, R in the compound formula of the structural formula I of generation
1For being selected from methyl, R
2And R
3Both are that hydrogen and X are fluorine.This compound has been proved has excellent anti-HIV-1 activity.Hydroxy-protective group P needs, and it is that the technician is known in the known art, because they avoid paying the productive rate that enhancement is provided in reaction and the reactions steps afterwards.As an example, suitable hydroxy-protective group can be an acyl group such as benzyloxy-carbonyl, methyl diphenyl carbethoxy, trityl oxygen carbonyl, right-nitro-benzyloxycarbonyl, valeryl, and 2,2, the 2-trichloro-ethoxycarbonyl; Aralkyl such as benzyl, diphenyl-methyl, trityl or right-nitrobenzyl or three organic group first silicon groups such as three (C
1-C
6) silica-based (as: the trimethylammonium first is silica-based, the silicoheptane base, the triisopropyl first is silica-based, the sec.-propyl dimethyl methyl is silica-based, the tert-butyl dimethyl methyl is silica-based for the alkyl first, methyl di-isopropyl first is silica-based or methyl two-tert-butyl first is silica-based), triaryl first silica-based (as: the triphenyl first is silica-based, three-right-xylyl first is silica-based) or three aralkyl first silica-based (as: the tribenzyl first is silica-based).The example of the suitable hydroxy-protective group of these and other such as methylsulfonyl, alkyl sulphonyl, aryl sulfonyl, and the method for their formation and removal is known in known art.Referring to: the blocking group in the organic synthesis, T.W.Greene, John Wiley ﹠amp; Sons, Nen York, 1981, the 2 chapters.Selected hydroxy-protective group is a kind of for what can preferably be easy to remove in the step (B) of reaction process.
At blocking group P is in the reactions steps (B) of trityl, preferably with a toluenesulphonic acids is carried out under envrionment temperature in methyl alcohol from about 1 hour to 24 hours, but normally between 18 hours and 24 hours, obtain the highest productive rate.
After further studying specification sheets of the present invention and appending claims, further purpose of the present invention and advantage will become more obvious to those skilled in the art.
The present invention will be described in more detail by following examples, but concrete enforcement is not to be restriction the present invention.
Embodiment 1.
5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides
To 200mg5 '-O-trityl group-2 '-deoxidation-2,3 '-be added in the 2.0M trimethyl aluminium of the 0.11ml in the toluene in the dehydration solution of chest (gland pyrimi piperidine deoxidating nucleus) glycosides in the 1%HF-of 5ml diox.Container is enclosed in 50 ℃ of heating 24 hours.Add 2ml water and the then filtration of 1g lime carbonate to reactant.The residue that filtrate evaporation is obtained on silica gel with 3: 1 methylene dichloride: the acetone chromatography obtain 28.7mg 5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
300 MHz
1H-NMR（DMSO，ppm）：11.40（s，1H），7.50（s，1H），7.45-7.25（m，15H），6.23（d of d，1H），5.43（d of d，1H），4.24（d，1H），3.35（d of d，1H）3.20（d of d，1H），2.6-2.3（m，2H），1.43（s，3H））。
Embodiment 2.
5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
To 1g 5 '-O-trityl-2 '-deoxidation-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides has 3%HF-1 at 13ml, is added in the 1.0M triethyl aluminum of the 3.2ml in the hexane in the solution in the 2-glycol dimethyl ether.With container airtight and 60-70 ℃ the heating 4 hours.The filter bed of this suspended substance by 2g lime carbonate filtered.Add 5ml methyl alcohol to filtrate, then evaporation obtains the 520mg residue, by high pressure liquid chromatography (HPLC) on silica gel with 3: 1 methylene dichloride: the acetone chromatography, show to contain 5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
300 MHz
1H-NMR(DMSO, ppm): 11.40(s, 1H), 7.50(s, 1H), 7.45-7.25(m, 15H) 6.23(d of d, 1H), 5.43(d of d, 1H), 4.24(d, 1H), 3.35(d of d, 1H) 3.20(d of d, 1H), 2.6-2.3(m, 2H), 1.43(s, 3H)); 2 ', 3 '-dideoxy-3 '-fluorothymidine, (300 MHz
1H-NMR(DMSO, ppm): 11.35(s, 1H), 7.7(s, 1H), 6.22(d of d, 1H), 5.32(d of d, 1H), 5.21(s, 1H), 4.09-4.2(m, 1H), 3.55-3.68(m, 2H), 2.2-2.5(m, 2H); ) and trityl alcohol m/e(EI)=244.
Embodiment 3.
2, ' 3, '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
To 1g 5 '-O-trityl group-2 '-deoxidation-2,3 '-the dehydration solution of chest (gland pyrimi piperidine deoxidating nucleus) glycosides in the 3%HF-of 13ml two-methyl ethyl ether is added in the diethyl aluminun fluoride solution of the 2.4M of the 1.3ml in the heptane.Reaction vessel is enclosed in 60-70 ℃ of heating 4 hours, and filters by 2g lime carbonate filter bed.Add 5ml methyl alcohol to filtrate and then obtain the 630mg solid residue by evaporation.This residue by HPLC on silica gel with 3: 1 methylene dichloride: acetone chromatography, demonstration be 5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
300 MHz
1H-NMR（DMSO，ppm）：11.40（s，1H），7.50（s，1H），7.45-7.25（m，15H），6.23（d of d，1H），5.43（d of d，1H），4.24（d，1H），3.35（d of d，1H）3.20（d of d，1H），2.6-2.3（m，2H），1.43（s，3H））。
2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;m/e（EI）＝244）
Mixture with trityl alcohol.Residue is dissolved in the methyl alcohol of the right-toluenesulphonic acids that contains catalytic amount and in stirring at room 24 hours, the residue that evaporation obtains on silica gel chromatography with 3: 1 methylene dichloride: the acetone chromatography obtains the required product of 182mg.
Embodiment 4.
5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-chlorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 103.4mg 5 '-O-trityl group-2 '-deoxidation-2,3 '-the dehydration solution of chest (gland pyrimi piperidine deoxidating nucleus) glycosides in the 3%HF-of 5ml diox adds the solution of diethyl aluminum chloride of the 1.0M of 55 μ l.Reaction vessel is airtight and in stirring at room 24 hours, and the water from 2ml to this mixture and the 1g lime carbonate that add then filter.The filtrate evaporation is obtained residue, this residue was with 3: 1 methylene dichloride: acetone is chromatography on silica gel, obtain isolating component 2 ', 3 '-dideoxy 3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides 26mg and 5-O-trityl, 2 ' 3 '-dideoxy-3 '-chlorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides 52mg.
Embodiment 5.
5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 579.5mg 5 '-O-methylsulfonyl-2 '-deoxidation 2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides is at the 3%HF-1 of 7ml, is added in the diethyl aluminun fluoride solution of the 2.4M of the 1.2ml in the heptane in the suspension of 2-glycol dimethyl ether.With reaction vessel airtight and 60-70 ℃ the heating 24 hours.The filter bed of the lime carbonate of this mixture by 1g filters, the filtrate evaporation obtain 343mg 5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides
300 MHz
1H-NMR（DMSO，ppm）：11.40（s，1H），7.52（s，1H），6.24（d of d，1H），5.37（d of d，1H），4.44（s，2H），4.40（m，1H），3.26（s，3H），2.2-2.6（m，2H），1.78（s，3H））.
Embodiment 6.
2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 200mg 2 '-deoxidation-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides adds the diethyl aluminum fluoride that 1.8ml is 1.0M in the suspension of the 3%HF-of 3ml diox.With container airtight and in 80 ℃ the heating 24 hours.This suspended substance filters by the lime carbonate filter bed, and the filtrate evaporation obtains 20mg, 2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;m/e（EI）＝244）.
Embodiment 7.
2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 1.5g 5 '-O-trityl group-2 '-deoxidation-2,3 '-solution of dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides in the 3%HF-of 15ml glycol dimethyl ether adds the solution of tri-propyl aluminum in toluene of the 1.0M of 4.8ml.Reaction vessel is airtight and in 65 ℃ of continuously stirring 1 hour.This mixture filters by the lime carbonate filter bed, and the filtrate evaporation obtains residue, this residue is dissolved in the methyl alcohol of the right-toluenesulphonic acids that contains catalytic amount, then in stirring at room 24 hours.The reaction mixture evaporation is obtained residue, this residue is dissolved in the 2-propyl alcohol of heat, cooling obtains 75mg2 ' then, 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;m/e（EI）＝244）.
Embodiment 8.
2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 10.0g 5 '-O-trityl group-2 '-deoxidation-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides is added dropwise to the solution of 2.4M diethyl aluminum fluoride in heptane of 13.3ml in greater than 5 minutes under the cooling of ice in the solution of the 3%HF-of 105ml glycol dimethyl ether.With container airtight and in 68 ℃ oil bath stirring heating 4 hours.This mixture is filtered by the lime carbonate filter bed, add 20ml methyl alcohol in the filtrate.With the evaporation of this mixture obtain residue be dissolved in contain 1g right-methyl alcohol of the 100ml of toluenesulphonic acids in and stirring at room 20 hours.Mixture is filtered, the filtrate evaporation obtains the 8.51g white solid, this white solid is dissolved in the methylene dichloride, and the methylene dichloride by 3: 1: acetone chromatography on silica gel obtains 1.78g 2 ' with the methylene dichloride elution, 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;m/e（EI）＝244）.
Embodiment 9.
5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 1.04g 5 '-O-trityl group-2 '-deoxidation-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides is at the 3%HF-1 of 10ml, the solution in the 2-glycol dimethyl ether adds 712.62mg three-uncle-butoxy aluminium.With container airtight and in 65 ℃ the heating 4 hours.High pressure liquid chromatography was with 4: 1 methylene dichloride on silica gel: acetone show have 5 '-O-trityl group-2 ', 3 '-dideoxy-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
Embodiment 10.
-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 205.3mg 2 '-deoxidation-2,3 '-solution of dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides in the 5ml glycol dimethyl ether adds the solution of 1.0M di-isopropyl alanate in tetrahydrofuran (THF) of 1ml.Stir after 30 minutes, with the 3%HF-glycol dimethyl ether solution adding of 5ml.Reaction vessel is airtight and stirred 17 hours in 70 ℃.15ml methyl alcohol and 4g lime carbonate are added, then filter, the filtrate evaporation obtained white solid, with this white solid by the dihydro methane of Magnesium Silicate q-agent column chromatography with 4: 1: the acetone purification, obtain 54.2mg 2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
Embodiment 11.
-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 523.4mg, 2.34mM 2 '-deoxidation-2 ', 3 '-two dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides be at 2ml 1, the 2-glycol dimethyl ether (add the solution of the 25.1% 3 hexyl aluminium of 1.03ml in the suspension at heptane.With mixture in stirring at room 4.5 hours and then in 65 ℃ the heating 15 minutes.The solution of the 3%HF/1.2-glycol dimethyl ether of 7ml added and with the mixture that produces in airtight container in 65 ℃ of heating 24 hours.The water and the 1g CaCO that add 2ml
3And use Na
2CO
3Regulate pH to neutral, mixture is filtered.The filtrate evaporation is obtained yellow solid, this yellow solid recrystallization from the 2-propyl alcohol is obtained 57mg 2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;
m/e（EI）＝244）.
Embodiment 12.
2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 10g, 45.5mM 2 '-deoxidation-2 ', 3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides is at 3%HF-1, adds 22.1g in the county's supernatant liquid in the 2-glycol dimethyl ether, the praseodynium aluminium of 68.1mM.This mixture after 2 hours, is added 100ml water and 35gCaCO in 90 ℃ of heating in encloses container
3, this suspension is filtered by hydrated magnesium silicate.With filtrate evaporation and adding 200ml water and 2g activated carbon.Mixture heating up is refluxed and filtration.Filtrate is evaporated to 2/3 volume and refilters.
Last filtrate evaporation is obtained 3.82g 2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;
m/e（EI）＝244）.
Embodiment 13.
2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
To 204mg, 0.72mM 5 '-O-ethanoyl-2 '-deoxidation-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides is at 3%HF/1, adds the solution of diethyl aluminum fluoride/heptane of the 2.4M of 0.46ml in the solution of 2-glycol dimethyl ether.This mixture was heated 24 hours at 58 ℃ in encloses container, add 2g CaCO
3, use Na
2CO
3Regulating pH filters to neutrality and with mixture.Filtrate evaporation also is dissolved in residue 3: 1 CH
1Cl
2The mixture neutralization of acetone is filtered by the silica gel filter bed.With filtrate evaporation obtain 160.5mg 5 '-O-ethanoyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.With this material dissolves at 5ml methyl alcohol and add 225mg K
2CO
3Stir after 10 minutes, evaporate with the solution filtration with filtrate.Residue is stirred into slurry and filtration at acetone.The filtrate evaporation is obtained 121mg 2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
（300 MHz
1H-NMR（DMSO，ppm）：11.35（s，1H），7.7（s，1H），6.22（d of d，1H），5.32（d of d，1H），5.21（s，1H），4.09-4.2（m，1H），3.55-3.68（m，2H），2.2-2.5（m，2H）;
m/e（EI）＝244）.
Embodiment 14.
5 '-O-methylsulfonyl-2 ' 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
In the container that 600ml stirs, be added in 10g 5 '-O-methylsulfonyl-2 in the 280ml diox '-dideoxy-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides, the 10%HF and three in 280ml diox, the 42.9ml Zai diox-just-hexyl aluminium.Container is airtight and stirred 3 hours at 77-84 ℃, then in envrionment temperature after 14 hours, 77-84 ℃ 3 hours.Return be chilled to envrionment temperature after, reactant impouring 30g lime carbonate in 50ml water, is stirred the slurry that produces 30 minutes and by the 10g filtered through silica gel.Filtrate is concentrated into about 50ml, adds 25ml water and continues to be concentrated into 25ml.Obtain 6.59g(62% by solid and the drying that filter to collect produces) 5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides, be cream-coloured solid.
Embodiment 15.
5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
With 0.2g 5 '-O-trityl group-2 '-deoxidation-2,3 '-mixture of dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides and 0.2g praseodynium aluminium breaks into slurry in the 5.2ml diox.Under agitation add the solution in the 10%HF Zai diox of 1.5ml.In 50-53 ℃ of heating 19 hours, cooling added 1ml water and then adds 0.8g CaCO with mixture
3And methylene dichloride.Mixture is filtered, the filter cake washing with acetone, and with isolating organic layer evaporate obtain 0.15g 5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
Embodiment 16.
5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
With 0.24g 5 '-O-trityl group-2 '-deoxidation-2,3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides and 0.22g aluminum isopropoxide handle with 10%HF at the mixture of 4.28g glycol dimethyl ether.This mixture heated 22 hours in 40-45 ℃ of oil bath.With the mixture cooling, add 0.2ml water and 1.0g lime carbonate.Mixture is filtered filter cake acetone and washed with dichloromethane.With filtrate evaporation obtain 0.16g 5 '-O-trityl group-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
Embodiment 17.
5 '-O-two methylsulfonyls-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
Adding 10g 5 '-O-methylsulfonyl-2 in an autoclave that stirs '-deoxidation-2 ', 3 '-dewater chest (gland pyrimi piperidine deoxidating nucleus) glycosides, 20.3g aluminum isopropoxide, 10%HF in the 7.3ml Zai diox and 128ml diox.With this still airtight and stir and be heated to about 90 ℃ 3 hours.Be cooled to the envrionment temperature button, with this mixture impouring to the mixture of 40g lime carbonate and 50ml water.With this slurry stir about 30 minutes, and by the B filtering.(4 * 25ml) wash filter cake with acetone.Solution evaporation is also broken into slurry with 100ml acetone to dry.The elimination insolubles and with filtrate be evaporated to drying obtain 9.05g 5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides, be a kind of solid.
Embodiment 18.
5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides
In an autoclave, add 5.0g 5 '-O-methylsulfonyl-2 '-deoxidation-2 ', 3 '-10%HF in dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides, 5.9g Acetyl Acetone aluminium, 85ml diox and the 20ml Zai diox.With solution be heated to 100-108 ℃ 11/4 hour.Be cooled to room temperature and use 10ml diox, 25ml water, 50ml acetone and adding 8.0g lime carbonate, stirred 30 minutes.With this mixture filtering, filter cake with washing with acetone and with filtrate be evaporated to drying obtain 6.0g 5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides
Embodiment 19.
5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides
With 5.0g '-O-methylsulfonyl-2 '-deoxidation-2 ', 3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides, 16.1g Acetyl Acetone aluminium and 5.0ml(30% pyridine, 70%HF) the 100ml diox in still in 88-93 ℃ of heating 3 hours.Still is cooled to room temperature and the content impouring is contained in the 50ml water of 15g lime carbonate.Under continuously stirring, add 21g lime carbonate.PH is 5 as a result.With this mixture by diatomite filtration and with washing with acetone several times with filter cake.With the filtrate evaporation, the residue that obtains is dissolved in the 100ml acetone and by cotton and filters.Obtain the required product of 4.4g with the filtrate evaporation and with residue vacuum-drying.
Embodiment 20.
5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
Adding 25g 5 '-O-methylsulfonyl-2 in the autoclave that stirs '-deoxidation-2 ', 3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides, the 2M three hexyl aluminium in the 83ml Zai diox, the mixture of the 70%HF of 98ml diox and 19ml and 30% pyridine.Still is airtight and be heated to 85-90 ℃ and kept 3 hours in about 90 ℃.Still is cooled in room temperature and the mixture of impouring 40g lime carbonate in 100ml water.With this mixture stir about 15 minutes, filtering and with acetone (4 * 25ml) washing leaching cakes.This solution is concentrated in the vacuum lower section, add 200ml water and this solution is further concentrated.This mixture is cooled to 0-5 ℃, filters, obtain the product of 22.2g with about 45ml cold water washing filter cake and drying.
Embodiment 21
5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
In an autoclave that stirs, add 1,000g 5 '-O-methylsulfonyl-2 '-deoxidation-2 ', 3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides, 6000ml diox, 1180g Acetyl Acetone aluminium, 100g difluoro hydrogenation ammonium (NH
4FHF) and 4, the 10%HF solution in the 000ml Zai diox.Still is airtight and stir and 85-90 ℃ of heating 3 hours.Still is cooled to 20-30 ℃ and impouring to 2, and 000g lime carbonate and 10 in the slurry of 000ml water, stirs this slurry 15-30 minute and passes through solids removed by filtration.Filter cake 7500ml washing with acetone, merging filtrate and washing lotion under reduced pressure are concentrated into the volume of 6-7.5 liter.Add 2 then, 000ml water also further is concentrated into the 7-7.5 liter with solution.This mixture is chilled to 0-5 ℃ and stirred 30-60 minute in 0-5 ℃.Product is filtered, uses the 1500ml cold water washing, and drying obtain 762g 5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides.
Embodiment 22.
5 '-O-methylsulfonyl-2 ', 3 '-dideoxy-3 '-fluorine chest (gland pyrimi piperidine deoxidating nucleus) glycosides:
Adding 10g 5 '-O-methylsulfonyl-2 in the autoclave of 300 milliliters stirrings '-deoxidation-2 ', 3 '-dehydration chest (gland pyrimi piperidine deoxidating nucleus) glycosides, 19.3 aluminum isopropoxide and 90ml diox.Behind the airtight still, add the mixture of the 30% pyridine 70%HF of 10.4ml, because heat release, temperature rises to about 58 ℃, and reactant is heated to 90 ℃ and stirred 3 hours in 90 ℃.After being cooled to room temperature, reactant is handled with the dilution of 50ml water and with 40g lime carbonate.Then stirred 20 minutes, and reactant was filtered solids washed with acetone.The filtrate that merges is concentrated into semisolid, adds 50ml acetone and also this solution is stripped to doing.The solid drying that produces is obtained the product of 10.8g.
Claims (10)
1, a kind of method that is prepared as follows the compound of structural formula:
Z is oxygen or CH in the formula
2R
1And R
2Can be identical or different, and be the group that is selected from the aryl that comprises that hydrogen, low alkyl group, halogen, alkenyl, aryl replace; R
3For being selected from the group that comprises hydrogen and halogen; And X is a halogen; It is characterized in that comprising the steps:
(a) with the compound of following structural formula:
P is selected to comprise the silica-based a kind of reagent with structural formula H-X of hydrogen, trityl group, anisole ylmethyl, ethanoyl, valeryl, methylsulfonyl or trialkyl first in the formula, and X is a halogen in the formula, in the presence of the reagent of following structural formula:
In the formula, R comprises (C for being selected from
1-C
12) alkyl side chain or non-side chain, (C
1-C
12) phenyl, hydrogen, carboxyl, benzyl, enol base, carbonyl, beta-diketon acidic group, the thiazolinyl of alkoxyl group side chain or non-side chain, phenyl or replacement, (C
1-C
12) group of sulfur phenenyl of sulfane base side chain or non-side chain, sulfur phenenyl or replacement; K and M identical or different comprise that for being selected from R and a kind of halogen, condition are that R, K and M are not hydrogen entirely, in a kind of inert organic solvents, mix,
(b) heating described compound and at 40-115 ℃ of about 1-24 hour to produce the compound of following structural formula:
And in the formula P for being different from hydrogen,
(c) remove described blocking group.
2, a kind of method that is prepared as follows the compound of structural formula II:
Z is oxygen or CH in the formula
2; R
1And R
2Can be identical or different and comprise: the group of the aryl of hydrogen, low alkyl group, halogen, alkenyl, aryl and replacement for being selected from; R
3For being selected from the group that comprises hydrogen and halogen; And X is halogen, it is characterized in that comprising the steps:
(a) with the compound of following structural formula:
P is that hydrogen or blocking group system are selected from trityl group in the formula, the group that methoxyl group trityl group, ethanoyl, valeryl, methylsulfonyl or trialkyl first are silica-based and a kind of reagent of structural formula H-X, and X is that halogen mixes mutually in the formula; In the presence of the reagent of following structural formula:
R comprises (C for being selected from the formula
1-C
12) alkyl side chain or non-side chain, (C
1-C
12) group of phenyl of alkoxyl group side chain or non-side chain, phenyl or replacement, hydrogen, carboxyl, benzyl, enol base, carbonyl, alkenyl, (C
1-C
12) group of sulfur phenenyl of sulfane base side chain or non-side chain, sulfur phenenyl or replacement, K and M can be identical or different and for to be selected from the group that comprises R and halogen, condition is that R, K and M are not hydrogen entirely, and in inert solvent:
(b) heating described compound and reagent and in 40-115 ℃ of about 1-24 hour, to obtain the compound of following structural formula:
And, in the formula P for being different from hydrogen,
(c) remove described blocking group.
3, method as claimed in claim 1 or 2 is characterized in that described reagent H-X is HF.
4, method as claimed in claim 1 or 2 is characterized in that described reagent:
Be trimethyl aluminium, triethyl aluminum, tri-propyl aluminum or three-uncle-butoxy aluminium, R, K and M are identical and equal methyl, ethyl, propyl group or uncle-butoxy in the formula.
5, method as claimed in claim 1 or 2 is characterized in that described reagent:
For R and M in the diisobutyl alanate formula are that isobutyl-K is a hydrogen.
6, method as claimed in claim 1 or 2 is characterized in that described reagent:
Be aluminum isopropoxide, in the formula R, K and M each be isopropoxy.
7, method as claimed in claim 1 or 2 is characterized in that described reagent:
Each is the 2.4-pentadione for R, K and M in the Acetyl Acetone aluminium formula.
8, method as claimed in claim 1 or 2, it is characterized in that described reagent HF for concentration in ether solvent 0.01 to 15%.
9, method as claimed in claim 1 or 2 is characterized in that described reagent HX is that HF is blended in the pyridine wherein that HF/ pyridine concentration ratio is the 70%HF/30% pyridine.
10, the method for claim 1 is characterized in that described difluoro hydrogenation ammonium is added in the reaction mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US56359690A | 1990-08-06 | 1990-08-06 | |
| US07/563,596 | 1990-08-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1058969A true CN1058969A (en) | 1992-02-26 |
| CN1031343C CN1031343C (en) | 1996-03-20 |
Family
ID=24251148
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91104951A Expired - Lifetime CN1031343C (en) | 1990-08-06 | 1991-07-18 | Process for preparation of deoxynucleosides |
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| Country | Link |
|---|---|
| EP (1) | EP0470355B1 (en) |
| JP (1) | JP3026861B2 (en) |
| KR (1) | KR0173319B1 (en) |
| CN (1) | CN1031343C (en) |
| AT (1) | ATE138927T1 (en) |
| AU (1) | AU649698B2 (en) |
| CA (1) | CA2048347C (en) |
| CZ (1) | CZ283988B6 (en) |
| DE (1) | DE69119994T2 (en) |
| DK (1) | DK0470355T3 (en) |
| ES (1) | ES2088443T3 (en) |
| FI (1) | FI102375B1 (en) |
| GR (1) | GR3020946T3 (en) |
| HU (1) | HU209310B (en) |
| IE (1) | IE912762A1 (en) |
| IL (1) | IL98685A (en) |
| NZ (1) | NZ239213A (en) |
| PL (1) | PL166101B1 (en) |
| PT (1) | PT98554B (en) |
| SK (1) | SK278598B6 (en) |
| ZA (1) | ZA916156B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL100480A0 (en) * | 1991-01-15 | 1992-09-06 | American Cyanamid Co | Process for the preparation of 3'-fluoropyrimidine nucleosides |
| GB9309787D0 (en) * | 1993-05-12 | 1993-06-23 | Rhone Poulenc Chemicals | Purification of fluoronucleosides |
| GB9309795D0 (en) * | 1993-05-12 | 1993-06-23 | Rhone Poulenc Chemicals | Preparation of flouro-compounds |
| ES2121204T3 (en) * | 1993-05-12 | 1998-11-16 | Rhodia Limited | PREPARATION OF FLUORO-NUCLEOSIDES AND INTERMEDIATES FOR USE IN IT. |
| JP3677790B2 (en) * | 1993-08-04 | 2005-08-03 | 味の素株式会社 | Nucleoside derivatives and process for producing the same |
| GB0608876D0 (en) | 2006-05-05 | 2006-06-14 | Medivir Ab | Combination therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3775397A (en) * | 1969-11-12 | 1973-11-27 | Akad Wissenschaften Ddr | Novel cytostatic 2',3'-dideoxy-3'-fluoropyrimidine-nucleosides |
| SE464168B (en) * | 1989-07-19 | 1991-03-18 | Bo Fredrik Oeberg | ANTIVIRAL COMPOSITION CONSISTING OF A 3'-FLUORO-2 ', 3'-DIDEOXYNUCLEOSIDE COMPOUND AND AND 2', 3'-DIDEOXYNUCLEOSIDE COMPOUND (EXAMPLE AZT) |
-
1991
- 1991-06-26 ES ES91110587T patent/ES2088443T3/en not_active Expired - Lifetime
- 1991-06-26 EP EP91110587A patent/EP0470355B1/en not_active Expired - Lifetime
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